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J Nucl Med. 2008; 49 (Supplement 1):105P
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Oncology-Basic Science: Therapy, Metrics & Intervention

Translational Nuclear Medicine - Imaging Biomarkers

Molecular imaging biomarkers to predict resistance to nucleoside analogs in cancer

Rachel Laing1, Martin Walter3, Jenny Shu4, Isabel Hildebrandt1, Charles Dumontet5, Nagichettiar Satyamurthy1, Harvey Herschman1, Johannes Czernin1 and Caius Radu2

1 Molecular and Medical Pharmacology; 2 Crump Inst for Molecular Imaging; 3 Ahmanson Biological Imaging Div; 4 Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, California; 5 INSERM, U de Lyon, Lyon, France

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Objectives: The nucleoside pro-drug analogs gemcitabine (dFdC) and cytarabine (Ara-C) depend on the intracellular activity of deoxycytidine kinase (dCK) for their activation and subsequent oncolytic effects. Loss of dCK is a major cause of resistance to these pro-drugs, and molecular biomarkers to predict this resistance before initiation of treatment are lacking.

Methods: We recently developed a novel positron emission tomography (PET) probe, [18F]FAC [1-(2’-deoxy-2’-fluoroarabinofuranosyl) cytosine], which is structurally and biochemically related to gemcitabine and Ara-C. We hypothesize that [18F]FAC PET can accurately measure cellular dCK activity and therefore predict gemcitabine/Ara-C resistance. To test our hypothesis, we established cell lines with varying dCK expression and activity levels, including gemcitabine resistant cell lines.

Results: Cells expressing active dCK showed a 40-fold increase in [3H]FAC uptake compared to dCK deficient cells (1288 fmols vs 34 fmols; p<0.001). Correspondingly, FAC phosphorylation was 52-fold higher in dCK positive cells compared to dCK deficient cells (62 fmols vs 1.2 fmols; p=0.028). In vivo, dCK positive tumors showed a ~4-fold higher [18F]FAC accumulation than dCK deficient tumors, for which [18F]FAC retention was indistinguishable from background uptake by the paravertebral soft tissue.

Conclusions: According to our data, [18F]FAC PET can be used for metabolic phenotyping of tumoral dCK activity. This suggests an important role for this novel PET probe in cancer diagnostics and therapeutic stratification of patients.





This Article
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Google Scholar
Right arrow Articles by Laing, R.
Right arrow Articles by Radu, C.
PubMed
Right arrow Articles by Laing, R.
Right arrow Articles by Radu, C.